1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → HCID 57395817, compound

HRID 1782563Notes

Reaction equation

HRID 1782563 reaction equation
[NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33](O)=[O:34])=[C:31]([CH3:39])[N:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:28][C:29]1[CH:37]=[C:36]([CH3:38])[C:32]([C:33]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:34])=[C:31]([CH3:39])[N:30]=1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 34465636-Chloro-2,4-dimethylnicotinic acidHCID 68972302HCID 68972302, compound

Product 1

HCID 57395817HCID 57395817, compoundYield 77.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-pyridin-3-ylmethyl-amine (0.78 g, 2.12 mmol) was dissolved in DCM (10 mL). 6-Chloro-2,4-dimethyl-nicotinic acid (474 mg, 1.2 eq.), HOBT (430 mg, 1.5 eq.), DIPEA (760 μL, 2 eq.), and EDCI (612 mg, 1.5 eq.) were added sequentially. The mixture was stirred at room temperature for 6 h, and then quenched with saturated NaHCO3 (20 mL). The pH of the equilibrated aqueous was adjusted to 8 with 1N HCl, and the mixture was extracted with DCM (200 mL in 5 extracts). The combined organic was dried (Na2SO4) and concentrated. The residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent to give 6-chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (0.88 g, 77%) as light brown foam. 1H NMR (δ, CDCl3): 8.66 (1 H, d, br, J=5.7 Hz), 8.51 (1 H, s), 8.44 (1 H, d, J=4.8 Hz), 7.61 (1 H, d, J=8.1 Hz), 7.20 (1 H, dd, J=7.8, 4.8 Hz), 7.01 (1 H, s), 6.73 (2 H, d, J=9.0 Hz), 6.62 (2 H, d, J=9.0 Hz), 3.88 (2 H, s, an overlapping 1H, m), 3.71 (3 H, s), 3.33 (2 H, pentet, J=13.5 Hz), 2.80 (3 H, m), 2.51 (3 H, s, an overlapping 1 H, m), 2.30 (3 H, s), 2.12 (1 H, t, J=11.4 Hz), 1.82-1.66 (3 H, m), 1.60-1.46 (1 H, m), 1.11 (1 H, qd, J=12.3, 3.6 Hz), 0.99 (3 H, d, J=6.6 Hz), 0.92 (1 H, qd, J=12.0, 3.0 Hz); 13C NMR (δ, CDCl3): 167.2, 155.4, 152.9, 150.2, 148.9, 148.1, 147.5, 142.5, 135.7, 134.8, 123.3, 122.5, 117.8, 114.6, 60.5, 58.1, 55.6, 52.1, 47.5, 43.6, 40.1, 30.7, 29.4, 22.1, 18.8, 13.4; ES-MS m/z 536.5 (M+1). Anal. Calcd. for (C30H38N5ClO2) 0.2(H2O): C, 66.76; H, 7.17; N, 12.98; Cl, 6.57. Found: C, 66.80; H, 7.00; N, 12.86; Cl, 6.55.

Workup

  1. customquenched with saturated NaHCO3 (20 mL)
  2. extractionthe mixture was extracted with DCM (200 mL in 5 extracts)
  3. dry with materialThe combined organic was dried (Na2SO4)
  4. concentrationconcentrated
  5. customThe residue was purified with flash chromatography on 150 mL silica using a gradient of 5%→10% MeOH in EtOAc containing 1% NH4OH as the eluent

Sources & evidence

ORD record
ord-faa93dd4e7334d8b9a9238aa79125fb0
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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